Tofogliflozin
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MedKoo CAT#: 319803

CAS#: 903565-83-3 (free)

Description: Tofogliflozin, also known as CSG 452, is a potent and high selective SGLT2 inhibitor under development the treatment of diabetes mellitus. Tofogliflozin improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Tofogliflozin dose-dependently suppressed glucose entry into tubular cells. High glucose exposure (30 mM) for 4 and 24 h significantly increased oxidative stress generation in tubular cells, which were suppressed by the treatment of tofogliflozin or an antioxidant N-acetylcysteine (NAC).

Chemical Structure

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Tofogliflozin
CAS# 903565-83-3 (free)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 319803
Name: Tofogliflozin
CAS#: 903565-83-3 (free)
Chemical Formula: C22H26O6
Exact Mass: 386.17
Molecular Weight: 386.444
Elemental Analysis: C, 68.38; H, 6.78; O, 24.84

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5mg USD 200 Ready to ship
10mg USD 350 Ready to ship
25mg USD 650 Ready to ship
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Related CAS #: 903565-83-3 (free)   1201913-82-7 (hydrate)    

Synonym: CSG452; CSG-452; CSG 452; R-7201; R 7201; R7201; Tofogliflozin

IUPAC/Chemical Name: (1S,3'R,4'S,5'S,6'R)-6-(4-ethylbenzyl)-6'-(hydroxymethyl)-3',4',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,2'-pyran]-3',4',5'-triol

InChi Key: VWVKUNOPTJGDOB-BDHVOXNPSA-N

InChi Code: InChI=1S/C22H26O6/c1-2-13-3-5-14(6-4-13)9-15-7-8-16-12-27-22(17(16)10-15)21(26)20(25)19(24)18(11-23)28-22/h3-8,10,18-21,23-26H,2,9,11-12H2,1H3/t18-,19-,20+,21-,22+/m1/s1

SMILES Code: O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@]21OCC3=C2C=C(CC4=CC=C(CC)C=C4)C=C3

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Product Data:
Product Data
Certificate of Analysis:
View CoA: current batch, Lot# A21C07B28
Safety Data Sheet (SDS):
View Safety Data Sheet (SDS)
Instruction:
View handling instruction
Biological target: A potent and highly specific sodium/glucose cotransporter 2(SGLT2) inhibitor.
In vitro activity: Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency. Reference: Yamane M, Kawashima K, Yamaguchi K, Nagao S, Sato M, Suzuki M, Honda K, Hagita H, Kuhlmann O, Poirier A, Fowler S, Funk C, Simon S, Aso Y, Ikeda S, Ishigai M. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica. 2015 Mar;45(3):230-8. doi: 10.3109/00498254.2014.976296. Epub 2014 Oct 28. PMID: 25350082.
In vivo activity: In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (α-methyl-d-glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG. Reference: Nagata T, Suzuki M, Fukazawa M, Honda K, Yamane M, Yoshida A, Azabu H, Kitamura H, Toyota N, Suzuki Y, Kawabe Y. Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys. Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1520-33. doi: 10.1152/ajprenal.00076.2014. Epub 2014 Apr 23. PMID: 24761001.

Preparing Stock Solutions

The following data is based on the product molecular weight 386.44 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: Yamane M, Kawashima K, Yamaguchi K, Nagao S, Sato M, Suzuki M, Honda K, Hagita H, Kuhlmann O, Poirier A, Fowler S, Funk C, Simon S, Aso Y, Ikeda S, Ishigai M. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica. 2015 Mar;45(3):230-8. doi: 10.3109/00498254.2014.976296. Epub 2014 Oct 28. PMID: 25350082.
In vitro protocol: Yamane M, Kawashima K, Yamaguchi K, Nagao S, Sato M, Suzuki M, Honda K, Hagita H, Kuhlmann O, Poirier A, Fowler S, Funk C, Simon S, Aso Y, Ikeda S, Ishigai M. In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP. Xenobiotica. 2015 Mar;45(3):230-8. doi: 10.3109/00498254.2014.976296. Epub 2014 Oct 28. PMID: 25350082.
In vivo protocol: Nagata T, Suzuki M, Fukazawa M, Honda K, Yamane M, Yoshida A, Azabu H, Kitamura H, Toyota N, Suzuki Y, Kawabe Y. Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys. Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1520-33. doi: 10.1152/ajprenal.00076.2014. Epub 2014 Apr 23. PMID: 24761001.

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1: Sadurní A, Gilmour R. Stereocontrolled Synthesis of 2-Fluorinated C-Glycosides. European J Org Chem. 2018 Aug 1;2018(27-28):3684-3687. doi: 10.1002/ejoc.201800618. Epub 2018 Jun 7. PubMed PMID: 30147438; PubMed Central PMCID: PMC6099233.

2: Ishihara H, Anai M, Seino H, Kitazawa T, Ohashi H, Ai M, Inoue M, Fujishiro M, Inazawa T, Kuroda H, Yamada M. Rationale and Design of the STOP-OB Study for Evaluating the Effects of Tofogliflozin and Glimepiride on Fat Deposition in Type 2 Diabetes Patients Treated with Metformin/DPP-4 Inhibitor Dual Therapy. Diabetes Ther. 2018 Aug 25. doi: 10.1007/s13300-018-0491-4. [Epub ahead of print] PubMed PMID: 30145651.

3: Ikeda S, Takano Y, Schwab D, Portron A, Kasahara-Ito N, Saito T, Iida S. Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Tofogliflozin (A SELECTIVE SGLT2 Inhibitor) in Patients with Type 2 Diabetes Mellitus. Drug Res (Stuttg). 2018 Aug 13. doi: 10.1055/a-0662-0209. [Epub ahead of print] PubMed PMID: 30103216.

4: Sakaeda T, Kobuchi S, Yoshioka R, Haruna M, Takahata N, Ito Y, Sugano A, Fukuzawa K, Hayase T, Hayakawa T, Nakayama H, Takaoka Y, Tohkin M. Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. Int J Med Sci. 2018 Jun 13;15(9):937-943. doi: 10.7150/ijms.22224. eCollection 2018. PubMed PMID: 30008607; PubMed Central PMCID: PMC6036094.

5: Kusunoki M, Natsume Y, Miyata T, Tsutsumi K, Oshida Y. Effects of Concomitant Administration of a Dipeptidyl Peptidase-4 Inhibitor in Japanese Patients with Type 2 Diabetes Showing Relatively Good Glycemic Control Under Treatment with a Sodium Glucose Co-Transporter 2 Inhibitor. Drug Res (Stuttg). 2018 Jul 2. doi: 10.1055/a-0585-0145. [Epub ahead of print] PubMed PMID: 29966149.

6: Bekki M, Tahara N, Tahara A, Igata S, Honda A, Sugiyama Y, Nakamura T, Sun J, Kumashiro Y, Matsui T, Fukumoto Y, Yamagishi S-I. Switching dipeptidyl peptidase-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 improves arterial stiffness evaluated by cardio-ankle vascular index in patients with type 2 diabetes: a pilot study. Curr Vasc Pharmacol. 2018 May 15. doi: 10.2174/1570161116666180515154555. [Epub ahead of print] PubMed PMID: 29766812.

7: Ouchi M, Oba K, Suganami H, Yoshida A, Fujita T, Suzuki T, Yasutake M, Kaku K. This is in reply to the Letter by Kahathuduwa et al. titled "Unaccounted for regression to the mean renders conclusion of article titled 'Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor Tofogliflozin' unsubstantiated". Diabetes Obes Metab. 2018 Aug;20(8):2041-2042. doi: 10.1111/dom.13347. Epub 2018 Jun 5. PubMed PMID: 29749099.

8: Kahathuduwa CN, Thomas DM, Siu C, Allison DB. Unaccounted for regression to the mean renders conclusion of article titled "Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin" unsubstantiated. Diabetes Obes Metab. 2018 Aug;20(8):2039-2040. doi: 10.1111/dom.13323. Epub 2018 May 3. PubMed PMID: 29660244; PubMed Central PMCID: PMC6043394.

9: Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, Tangri N, Goh SY, Thuresson M, Chen H, Surmont F, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 Jun 12;71(23):2628-2639. doi: 10.1016/j.jacc.2018.03.009. Epub 2018 Mar 11. PubMed PMID: 29540325.

10: Ito S, Hosaka T, Yano W, Itou T, Yasumura M, Shimizu Y, Kobayashi H, Nakagawa T, Inoue K, Tanabe S, Kondo T, Ishida H. Metabolic effects of Tofogliflozin are efficiently enhanced with appropriate dietary carbohydrate ratio and are distinct from carbohydrate restriction. Physiol Rep. 2018 Mar;6(5). doi: 10.14814/phy2.13642. PubMed PMID: 29520981; PubMed Central PMCID: PMC5843757.

11: Kamei S, Iwamoto M, Kameyama M, Shimoda M, Kinoshita T, Obata A, Kimura T, Hirukawa H, Tatsumi F, Kohara K, Nakanishi S, Mune T, Kaku K, Kaneto H. Effect of Tofogliflozin on Body Composition and Glycemic Control in Japanese Subjects with Type 2 Diabetes Mellitus. J Diabetes Res. 2018 Jan 8;2018:6470137. doi: 10.1155/2018/6470137. eCollection 2018. PubMed PMID: 29507863; PubMed Central PMCID: PMC5817268.

12: Horikawa Y, Enya M, Komagata M, Hashimoto KI, Kagami M, Fukami M, Takeda J. Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report. Diabetes Ther. 2018 Feb;9(1):421-426. doi: 10.1007/s13300-018-0369-5. Epub 2018 Jan 15. PubMed PMID: 29335890; PubMed Central PMCID: PMC5801255.

13: Terauchi Y, Tamura M, Senda M, Gunji R, Kaku K. Long-term safety and efficacy of tofogliflozin as add-on to insulin in patients with type 2 diabetes: Results from a 52-week, multicentre, randomized, double-blind, open-label extension, Phase 4 study in Japan (J-STEP/INS). Diabetes Obes Metab. 2018 May;20(5):1176-1185. doi: 10.1111/dom.13213. Epub 2018 Feb 11. PubMed PMID: 29316236; PubMed Central PMCID: PMC5947124.

14: Matsuba R, Matsuba I, Shimokawa M, Nagai Y, Tanaka Y. Tofogliflozin decreases body fat mass and improves peripheral insulin resistance. Diabetes Obes Metab. 2018 May;20(5):1311-1315. doi: 10.1111/dom.13211. Epub 2018 Feb 4. PubMed PMID: 29316197; PubMed Central PMCID: PMC5947308.

15: Ouchi M, Oba K, Kaku K, Suganami H, Yoshida A, Fukunaka Y, Jutabha P, Morita A, Otani N, Hayashi K, Fujita T, Suzuki T, Yasutake M, Anzai N. Uric acid lowering in relation to HbA1c reductions with the SGLT2 inhibitor tofogliflozin. Diabetes Obes Metab. 2018 Apr;20(4):1061-1065. doi: 10.1111/dom.13170. Epub 2018 Jan 8. PubMed PMID: 29171930; PubMed Central PMCID: PMC5887894.

16: Cai X, Yang W, Gao X, Chen Y, Zhou L, Zhang S, Han X, Ji L. The Association Between the Dosage of SGLT2 Inhibitor and Weight Reduction in Type 2 Diabetes Patients: A Meta-Analysis. Obesity (Silver Spring). 2018 Jan;26(1):70-80. doi: 10.1002/oby.22066. Epub 2017 Nov 22. PubMed PMID: 29165885.

17: Tobe K, Suganami H, Kaku K. Sodium-glucose cotransporter 2 inhibitor, tofogliflozin, shows better improvements of blood glucose and insulin secretion in patients with high insulin levels at baseline. J Diabetes Investig. 2018 Jul;9(4):862-869. doi: 10.1111/jdi.12761. Epub 2017 Nov 13. PubMed PMID: 29032638; PubMed Central PMCID: PMC6031493.

18: Obara K, Shirakami Y, Maruta A, Ideta T, Miyazaki T, Kochi T, Sakai H, Tanaka T, Seishima M, Shimizu M. Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice. Oncotarget. 2017 Apr 6;8(35):58353-58363. doi: 10.18632/oncotarget.16874. eCollection 2017 Aug 29. PubMed PMID: 28938561; PubMed Central PMCID: PMC5601657.

19: Sawada Y, Izumida Y, Takeuchi Y, Aita Y, Wada N, Li E, Murayama Y, Piao X, Shikama A, Masuda Y, Nishi-Tatsumi M, Kubota M, Sekiya M, Matsuzaka T, Nakagawa Y, Sugano Y, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yagyu H, Kawakami Y, Kadowaki T, Shimano H, Yahagi N. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry. Biochem Biophys Res Commun. 2017 Nov 4;493(1):40-45. doi: 10.1016/j.bbrc.2017.09.081. Epub 2017 Sep 18. PubMed PMID: 28928093.

20: Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, Umayahara Y, Kaneto H, Osonoi T, Yamamoto T, Kuribayashi N, Maeda K, Yokoyama H, Kosugi K, Ohtoshi K, Hayashi I, Sumitani S, Tsugawa M, Ohashi M, Taki H, Nakamura T, Kawashima S, Sato Y, Watada H, Shimomura I; UTOPIA study investigators. Rationale, Design, and Baseline Characteristics of the Utopia Trial for Preventing Diabetic Atherosclerosis Using an SGLT2 Inhibitor: A Prospective, Randomized, Open-Label, Parallel-Group Comparative Study. Diabetes Ther. 2017 Oct;8(5):999-1013. doi: 10.1007/s13300-017-0292-1. Epub 2017 Sep 1. PubMed PMID: 28864997; PubMed Central PMCID: PMC5630549.